Discovery of a novel series of imidazo[1',2':1,6]pyrido[2,3-d]pyrimidin derivatives as potent cyclin-dependent kinase 4/6 inhibitors

  • Eur J Med Chem. 2020 May 1;193:112239. doi: 10.1016/j.ejmech.2020.112239.
Chen Shi  1 ,  Qian Wang  1 ,  Xuemei Liao  1 ,  Hui Ge  1 ,  Guoyong Huo  1 ,  Leduo Zhang  1 ,  Na Chen  1 ,  Xiong Zhai  1 ,  Yuan Hong  1 ,  Li Wang  1 ,  Zhe Wang  1 ,  Weijun Shi  1 ,  Yu Mao  1 ,  Jianxin Yu  1 ,  Ying Ke  2 ,  Guangxin Xia  3
Affiliations
  • 1. Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 5, No. 898 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai, 201203, PR China.
  • 2. Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 5, No. 898 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai, 201203, PR China. Electronic address: [email protected].
  • 3. Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 5, No. 898 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai, 201203, PR China. Electronic address: [email protected].
PMID: 32200202 DOI: 10.1016/j.ejmech.2020.112239
Abstract

CDK4/6 has been identified as an attractive therapeutic target for treatment of Cancer. For unmet clinical needs, a novel class of imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives, which had distinctive triheteroaryl structure, had been discovered as CDK4/6 inhibitors. The compounds 10b and 10c, displayed the low nanomolar range activities on CDK4/6, desirable antiproliferative activities, excellent metabolic properties, and acceptable pharmacokinetic characters. In Colo-205 and U87MG xenograft models, compounds 10b and 10c also showed significant tumor growth inhibitions with controllable toxicities. All data confirmed that imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives 10b and 10c could be promising drug candidates for Cancer therapy.

Keywords
Antitumor; CDK4/6 inhibitors; Cell cycle.
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